1. Field of the Invention
This invention relates to a novel pharmaceutical composition which has excellent anti-inflammatory, analgesic and antipyretic activities and can also be administered parenterally, a method of treating inflammation, pain, and fever by using the composition, and a process for preparation of the composition.
2. Description of the Prior Art
4-Biphenylylacetic acid is a known compound having strong anti-inflammatory, analgesic and antipyretic activities (see U.S. Pat. No. 3,784,704). It is known, however, that oral or parenteral administration of 4-biphenylylacetic acid may sometimes be accompanied by ulceration or bleeding of the digestive organs. Hence, in spite of its excellent antiinflammatory, analgesic and antipyretic activities, it has not yet been used in clinical therapy as a practical drug. In order to reduce the side-effects of 4-biphenylylacetic acid while retaining its excellent pharmacological activities, 4-(4-biphenyl)-4-oxobutyric acid (common name: fenbufen; tradename NAPANOL.RTM., CINOPAL.RTM.) of the following formula ##STR2## was developed on the basis of the pro-drug theory (see Arzneimittel Forschung, 30 (1), 693-746, 1980), and this compound has been widely used clinically as an orally administrable anti-inflammatory, analgesic and antipyretic agents.
Fenbufen exhibits its anti-inflammatory, analgesic and antipyretic effects after it is converted to 4-biphenylylacetic acid within the body. Metabolization to the active substance, 4-biphenylylacetic acid, requires time and its effects appear somewhat slowly.
The side-effects of fenbufen on the digestive organs are considerably reduced as compared with conventional non-steroidal anti-inflammatory agents. But it is better to use with caution when applied to patients with a history of peptic ulcer or administered in large amounts.
Recently, the targeting therapy in which a drug is administered as a dissolved form in lipid particles of a lipid emulsion has been proposed and aroused much interest. This therapy utilizes the property of lipid particles, like liposome, to be taken into the reticuloendothelial system or inflamed cells. When a lipid-soluble drug dissolved in such lipid particles is administered, the lipid particles act as a drug carrier to carry the drug selectively to a specific site where the effect of the drug is exhibited concentratingly.
As such drugs, emulsions obtained by incorporating dexamethasone palmitate, ibuprofen, flufenamic acid, indomethacine ester, prostaglandin E.sub.1, and ketoprofen or its alkyl esters in lipid particles and emulsifying the lipid particles in water have been proposed [see, for example, A. Yanagawa, Japanese Journal of Inflammation, vol. 2, No. 3, Summer (1982), pages 251-257, Japanese Laid-Open Patent Publications Nos. 16818/1982, 59912/1983, 201712/1983, 222014/1983, and 13720/1984]. Among them, dexamethasone palmitate and prostaglandin E.sub.1 are lipid soluble and have successfully been formed into stable lipid emulsions. They are being clinically tested for administration to humans. The other drugs do not have sufficient solubility in oils or fats such as soybean oil. Then lipid emulsions having low concentrations of drug for animal tests can be prepared from these drugs, but no stable lipid emulsion having a sufficient concentration of the active compound to produce a satisfactory clinical effect has been obtained from them. Hence, the work to develop such lipid emulsions has been suspended.
Thus, the prior art has not given sufficient results in the preparation of lipid emulsions although an excellent therapeutic effect will be expected from the administration of drugs having anti-inflammatory, analgesic and antipyretic activities as lipid emulsions. It has been strongly desired therefore to develop a drug composition which can rapidly produce effects without an impairment in anti-inflammatory, analgesic and antipyretic activities with a minimum of the aforesaid side effects.